Imprinted genes in mouse placental development and the regulation of fetal energy stores

in Reproduction

Imprinted genes, which are preferentially expressed from one or other parental chromosome as a consequence of epigenetic events in the germline, are known to functionally converge on biological processes that enable in utero development in mammals. Over 100 imprinted genes have been identified in the mouse, the majority of which are both expressed and imprinted in the placenta. The purpose of this review is to provide a summary of the current knowledge regarding imprinted gene function in the mouse placenta. Few imprinted genes have been assessed with respect to their dosage-related action in the placenta. Nonetheless, current data indicate that imprinted genes converge on two key functions of the placenta, nutrient transport and placental signalling. Murine studies may provide a greater understanding of certain human pathologies, including low birth weight and the programming of metabolic diseases in the adult, and complications of pregnancy, such as pre-eclampsia and gestational diabetes, resulting from fetuses carrying abnormal imprints.

Abstract

Imprinted genes, which are preferentially expressed from one or other parental chromosome as a consequence of epigenetic events in the germline, are known to functionally converge on biological processes that enable in utero development in mammals. Over 100 imprinted genes have been identified in the mouse, the majority of which are both expressed and imprinted in the placenta. The purpose of this review is to provide a summary of the current knowledge regarding imprinted gene function in the mouse placenta. Few imprinted genes have been assessed with respect to their dosage-related action in the placenta. Nonetheless, current data indicate that imprinted genes converge on two key functions of the placenta, nutrient transport and placental signalling. Murine studies may provide a greater understanding of certain human pathologies, including low birth weight and the programming of metabolic diseases in the adult, and complications of pregnancy, such as pre-eclampsia and gestational diabetes, resulting from fetuses carrying abnormal imprints.

Keywords:

Introduction

The first evidence that both parental genomes are required for correct extraembryonic development in mammals came from studies on uniparental embryos generated by microsurgical manipulation of newly fertilised mouse embryos. Gynogenetic and parthenogenetic (two maternal genomes) embryos appear relatively normal but are growth restricted and die around embryonic day (E) 10 with abnormal development of the extraembryonic tissue. In contrast, androgenetic (two paternal genomes) embryos are both developmentally delayed and growth restricted, dying around E8.5, with an abundance of hyperplastic extraembryonic tissue (Kaufman et al. 1977, Surani & Barton 1983, Barton et al. 1984, McGrath & Solter 1984, Surani et al. 1986). Studies of uniparental disomic (UPD) embryos further highlighted the functional requirement for both parental genomes at certain chromosomal regions in placental development (Cattanach & Kirk 1985, Searle & Beechey 1990, McLaughlin et al. 1996, Cattanach et al. 2004). To date, over 100 imprinted genes have been identified in the mouse, the majority of which are both expressed and imprinted in the placenta (Table 1). Furthermore, X-linked genes that undergo inactivation can also be considered imprinted in the mouse placenta (Takagi & Sasaki 1975, West et al. 1977).

Table 1

Expression and imprinting of autosomal genes in the mouse placenta.

GeneActive alleleChrPlacental expressionPlacental imprintingPlacenta functional dataCommentsReferences
Gpr1P1YesBiallelicNoBiallelic in E13.5 placentaHiura et al. (2010) and Okae et al. (2012)
Imprinted only in kidney
Zdbf2P1YesConflicting dataNoImprinted E13.5 and E17.5 placentaBabak et al. (2008), Kobayashi et al. (2009), Hiura et al. (2010), Wang et al. (2011) and Okae et al. (2012)
Imprinted in E9.5 embryo
Biallelic in E15.5 placenta
Sfmbt2P2YesImprintedNoImprinted in early embryo and placentaKuzmin et al. (2008), Wang et al. (2011) and Okae et al. (2012)
Biallelic in embryo from ∼E7.5
Wt1M2Yes (decidua)Conflicting dataNoPreviously reported placental allelic bias probably due to contamination with decidual cellsBrideau et al. (2010a) and Okae et al. (2012)
Biallelic in E9.0 placenta
GatmM2Yes (decidua)Conflicting dataNoPreviously reported placental imprinting possibly due to contamination with decidual cellsSandell et al. (2003) and Okae et al. (2012)
Biallelic in E9.0 placenta
H13M2YesImprintedNoImprinted in E13.5 placenta and embryoWood et al. (2007b) and Wang et al. (2011)
Mcts2P2Not reportedNot reportedNoImprinted in E13.5 embryo and newborn brainWood et al. (2007b)
Biallelic in testes
NnatP2YesImprintedNoImprinted in E17.5 placenta and brainKagitani et al. (1997), Kikyo et al. (1997) and Wang et al. (2011)
BlcapM2YesBiallelicNoImprinted in brainSchulz et al. (2009), Wang et al. (2011) and Okae et al. (2012)
Potentially a consequence of transcript interference from maternal Nnat expression
Zfp64P2YesImprintedNoImprinted in E17.5 placentaWang et al. (2011)
GnasM2YesBiallelicNoImprinted in adipose tissueYu et al. (1998) and Okae et al. (2012)
Biallelic in kidney
NespM2YesImprintedNoImprinted in placenta and embryoPeters et al. (1999) and Wang et al. (2011)
NespasP2YesImprintedNoImprinted in E13.5 placenta and E15.5 embryoWroe et al. (2000) and Okae et al. (2012)
GnasxlP2Not reportedNot reportedNoImprinted in E11.5 embryoPeters et al. (1999)
Ex1AP2Not reportedNot reportedNoImprinted in brown adipose tissue (BAT)Liu et al. (2000)
Phf17P3YesImprintedNoImprinted in E17.5 placentaWang et al. (2011)
Magi2M5YesImprintedNoImprinted in E14.5 and E17.5 placentaBarbaux et al. (2012)
Htra3M5Yes (decidua)ImprintedNoImprinting reported in E17.5 placenta but expression restricted to deciduaNie et al. (2006) and Wang et al. (2011)
CalcrM6Not reportedNot reportedNoImprinted in brainHoshiya et al. (2003)
Biallelic in all other tissues examined
Tfpi2M6Yes (decidua)Imprinted (TS cells)NoPlacental imprint masked by decidual contaminationMonk et al. (2008) and Okae et al. (2012)
Imprinted in TS cells
Biallelic in embryo
Casd1M6YesConflicting dataNoImprinted in E13.5 placentaOno et al. (2003), Babak et al. (2008) and Okae et al. (2012)
Biallelic in E10 and E13 placentae
Imprinted in embryo
SgceP6YesImprintedNoImprinted in placenta, embryo and adultPiras et al. (2000), Monk et al. (2008), Wang et al. (2011) and Okae et al. (2012)
Peg10P6YesImprintedYesImprinted in placenta and fetal brainOno et al. (2003), Wang et al. (2011) and Okae et al. (2012)
Ppp1r9aM6YesImprintedNoImprinted in placenta and embryoOno et al. (2003), Nakabayashi et al. (2004), Wang et al. (2011) and Okae et al. (2012)
Biallelic in neonate
Pon3M6Yes (decidua)Conflicting dataNoPreviously reported placental allelic bias probably due to contamination with decidual cellsOno et al. (2003) and Okae et al. (2012)
Biallelic in E9.0 placenta
Pon2M6Yes (decidua)Conflicting dataNoImprinted in E10 placenta and E13 yolk sacOno et al. (2003), Wang et al. (2011) and Okae et al. (2012)
Conflicting data from E13.5 placenta following embryo transfer to eliminate decidual contamination
Biallelic in E17.5 placenta and neonate
Biallelic in TS cells
Asb4M6YesImprintedNoImprinted in E9.5 and E15.5 placenta and embryoMizuno et al. (2002) and Wang et al. (2011)
Peg1/MestP6Fetal vasculature onlyImprintedYesImprinted in E13.5 placenta and E9.5 embryoKaneko-Ishino et al. (1995), Mayer et al. (2000), Wang et al. (2011) and Okae et al. (2012)
Copg2as1P6Not reportedNot reportedNoImprinted in embryos, neonates and adultLee et al. (2000)
Copg2as2P6YesImprintedNoImprinted in E13.5 placenta, from ∼E13.5 in embryos and in neonate and adultLee et al. (2000) and Okae et al. (2012)
Copg2M6YesBiallelicNoBiallelic in E13.5 placentaLee et al. (2000) and Okae et al. (2012)
Imprinted in embryo and brain
Klf14M6YesImprintedNoImprinted in all embryo and placentaParker-Katiraee et al. (2007) and Wang et al. (2011)
Nap1l5P6Yes (low)Not reportedNoImprinted in brainSmith et al. (2003) and Davies et al. (2004)
Cntn3M6E13.5: noUnconfirmedNoImprinted in E17.5 placentaBrideau et al. (2010a) and Okae et al. (2012)
E17.5: yes?Biallelic in E17.5 brain
Not expressed in E13.5 placenta
Klrb1fM6E13.5: noUnconfirmedNoImprinted in E17.5 placentaBrideau et al. (2010a) and Okae et al. (2012)
E17.5: yes?Biallelic in E17.5 brain
Not expressed in E13.5 placenta
Zim2M7Not reportedNot reportedNoImprinted in brainKim et al. (2004)
Biallelic in testes
Zim1M7YesImprintedNoImprinted in E13.5 and E17.5 placenta, embryo and neonateKim et al. (1999), Wang et al. (2011) and Okae et al. (2012)
Biallelic in neonatal and adult brain
Peg3asP7Not reportedNot reportedNoBrain-specific expression and imprintingChoo et al. (2008)
Peg3P7YesImprintedYesImprinted in placenta and brainKaneko-Ishino et al. (1995), Kuroiwa et al. (1996), Wang et al. (2011) and Okae et al. (2012)
Usp29P7YesImprintedNoImprinted in placenta, embryoKim et al. (2000), Wang et al. (2011) and Okae et al. (2012)
Imprinted in neonatal and adult brain
Zim3M7Not reportedNot reportedNoImprinted in testesKim et al. (2001)
Zfp264P7Not reportedNot reportedNoImprinted in brain and testesKim et al. (2001)
AxlM7YesImprintedNoImprinted in extraembryonic tissue until mid gestationChoufani et al. (2011)
Biallelic in embryo
Atp10aM7YesBiallelicNoImprinted in some brain regionsKashiwagi et al. (2003) and Okae et al. (2012)
Biallelic in E13.5 placenta
Ube3aM7YesBiallelicNoImprinted in brainMiura et al. (2002), Yamasaki et al. (2003) and Okae et al. (2012)
Biallelic in E13.5 placenta
Ube3a-asP7Not reportedNot reportedNoImprinted in brain (overlapping expression with Ube3a)Yamasaki et al. (2003)
IpwP7Not reportedNot reportedNoImprinted in adultWevrick & Francke (1997)
Snord115P7NoNoBrain-specific expression and imprintingCavaille et al. (2000)
Snord116P7NoNoBrain-specific expression and imprintingCavaille et al. (2000)
Snord64P7NoNoBrain-specific expression and imprintingCavaille et al. (2000)
Snrpn/SnurfP7YesImprinted (TS Cells)NoImprinted in all tissues examined from ∼E7.5Leff et al. (1992), Barr et al. (1995), Gray et al. (1999), de los Santos et al. (2000) and Fortier et al. (2008)
Placental imprinting analysis complicated by maternal contamination
Imprinted in TS cells
Pec2P7Not reportedNot reportedNoImprinted in neonatal CNSBuettner et al. (2005) and Schulz et al. (2006)
Pec3P7Not reportedNot reportedNoImprinted in neonatal CNSBuettner et al. (2005) and Schulz et al. (2006)
NdnP7YesConflicting dataNoImprinted in brainMacDonald & Wevrick (1997), Wang et al. (2011) and Okae et al. (2012)
Imprinted in E17.5 placenta
Biallelic in E13.5 placenta
Magel2P7YesImprintedNoImprinted in E17.5 placenta and adult brainBoccaccio et al. (1999) and Wang et al. (2011)
Mkrn3/Zfp127P7Not reportedNot reportedNoImprinted in brain, heart and kidneyHershko et al. (1999) and Jong et al. (1999)
Zfp127asP7Not reportedNot reportedNoVery low expression relative to Mkrn3Cattanach et al. (1997) and Jong et al. (1999)
Peg12P7YesBiallelicNoImprinted in brainChai et al. (2001) and Kobayashi et al. (2002)
Biallelic in placenta
Art5M7E13.5: noUnconfirmedNoImprinted in E17.5 placentaBrideau et al. (2010a) and Okae et al. (2012)
E17.5: yes?Biallelic in E17.5 brain
Not expressed in E13.5 placenta
Ampd3M7Yes (decidua)Conflicting dataNoPreviously reported placental imprinting possibly due to contamination with decidual cellsSchulz et al. (2006) and Okae et al. (2012)
Biallelic in E9.0 placenta
Inpp5f_v2P7NoNoBrain-specific expression and imprintingChoi et al. (2005)
Inpp5f_v3P7NoNoBrain-specific expression and imprintingWood et al. (2007a) and Yan et al. (2011)
H19M7YesImprintedYesImprinted in placenta and embryoBartolomei et al. (1991), Svensson et al. (1998), Wang et al. (2011) and Okae et al. (2012)
Igf2asP7YesImprintedNoImprinted in E17.5 placentaMoore et al. (1997) and Wang et al. (2011)
Igf2P7YesImprintedYesImprinted in placenta and embryoDeChiara et al. (1991), Wang et al. (2011) and Okae et al. (2012)
Restricted biallelic expression in adult
Ins2P7Not reportedNot reportedNoImprinted in yolk sacDeltour et al. (1995)
ThM7YesImprintedHomozygous lethalImprinted in placentaZhou et al. (1995) and Okae et al. (2012)
Ascl2M7YesImprintedYesImprinted in placenta from ∼E8.5Guillemot et al. (1995) and Okae et al. (2012)
Tspan32M7Yes (TS cells)Imprinted (TS cells)NoImprinted in TS cellsOkae et al. (2012)
Cd81M7YesImprintedNoImprinted in placenta and embryo until ∼E8.5Caspary et al. (1998)
Tssc4M7YesImprintedNoImprinted in E13.5 placentaOkae et al. (2012)
Kcnq1M7YesImprintedNoImprinted in placentaGould & Pfeifer (1998), Umlauf et al. (2004) and Wang et al. (2011)
Biallelic in yolk sac at E12.5
Imprinted in early embryo, progressively biallelic
Kcnq1ot1P7YesImprintedYesImprinted in placenta and embryoSmilinich et al. (1999), Mancini-DiNardo et al. (2003, 2006) and Okae et al. (2012)
Cdkn1cM7YesImprintedYesImprinted in placenta, embryo and adultHatada & Mukai (1995), Takahashi et al. (2000) and Wang et al. (2011)
Slc22a18M7YesImprintedNoStrong imprinting in placenta and embryoDao et al. (1998) and Wang et al. (2011)
Weak imprinting in adult tissues
Phlda2M7YesImprintedYesImprinted in placenta and embryoQian et al. (1997)
Low-level expression and weak imprinting in adult
Nap1l4M7YesConflicting dataNoImprinted in E12.5 placentaEngemann et al. (2000), Umlauf et al. (2004) and Okae et al. (2012)
Biallelic in E9.0, E13.5 and E17.5 placenta
Biallelic in embryo
Tnfrsf23M7Decidua onlyImprintedNoPlacental imprinting reported but expression restricted to deciduasClark et al. (2002)
Osbpl5M7Yes (decidua)Conflicting dataNoPreviously reported placental imprinting possibly due to contamination with decidual cellsEngemann et al. (2000), Higashimoto et al. (2002) and Okae et al. (2012)
Biallelic in E9.0 placenta
Dhcr7M7Yes (decidua)Conflicting dataNoPreviously reported placental imprinting possibly due to contamination with decidual cellsSchulz et al. (2006) and Okae et al. (2012)
Biallelic in E9.0 placenta
Ano1M7YesImprintedNoImprinted in E13.5 placenta and TS cellsOkae et al. (2012)
Biallelic in embryo, yolk sac and adult
Gab1P8YesImprintedHomozygous null onlyImprinted in placenta and TS cellsOkae et al. (2012)
Biallelic in E13.5 embryo and yolk sac and adult
mir184P9No (brain specific)NoBrain-specific expression and imprintingNomura et al. (2008)
A19P9No (brain specific)NoBrain-specific expression and imprintingde la Puente et al. (2002)
AK029869P9No (brain specific)NoImprinted in embryonic, neonatal and adult brainBrideau et al. (2010b)
Rasgrf1P9YesImprintedNoImprinted in placenta, neonatal brain, adult brain, heart and stomachPlass et al. (1996) and Dockery et al. (2009)
Biallelic in thymus, testis and ovaries
Mstr1M9Yes (decidua)Conflicting dataNoPreviously reported placental imprinting probably due to contamination with decidual cellsBrideau et al. (2010a) and Okae et al. (2012)
Biallelic in E9.0 placenta
Plagl1/Zac1P10YesImprintedYesImprinted in E13.5 and E17.5 placenta and embryoPiras et al. (2000), Wang et al. (2011) and Iglesias-Platas et al. (2012)
Imprinted in adult, except liver
Phactr2M10YesImprintedNoImprinted in E17.5 placentaWang et al. (2011)
DcnM10Yes (decidua)Conflicting dataNoPreviously reported placental imprinting probably due to contamination with decidual cellsMizuno et al. (2002) and Okae et al. (2012)
Biallelic in E9.0 placenta
DdcP11Yes (low)BiallelicNoBiallelic in placentaMenheniott et al. (2008) and Shiura et al. (2009)
Imprinted in heart, neonatal brain and liver
Grb10M11YesImprintedYesImprinted in E13.5 and E17.5 placenta and embryoMiyoshi et al. (1998), Charalambous et al. (2010), Wang et al. (2011) and Okae et al. (2012)
CoblM11YesBiallelicNoBiallelic in placenta, embryo and neonateShiura et al. (2009)
Imprinted in yolk sac
Zrsr1P11YesImprintedNoImprinted in E13.5 and E17.5 placentaHayashizaki et al. (1994), Hatada et al. (1995), Wang et al. (2004, 2011) and Okae et al. (2012)
Imprinted in embryonic and neonatal brain
Imprinted in adult
Commd1M11YesBiallelicHomozygous lethalBiallelic in E13.5 placentaWang et al. (2004, 2008) and Okae et al. (2012)
Imprinted in adult brain
ScinM12Yes (decidua)Conflicting dataNoPreviously reported placental imprinting probably due to contamination with decidual cellsBrideau et al. (2010a) and Okae et al. (2012)
Biallelic in E9.0 placenta
BegainP12YesBiallelicNoBiallelic in E13.5 placentaTierling et al. (2009) and Okae et al. (2012)
Imprinted expression of one transcript in brain
Dlk1P12YesImprintedYesImprinted E12.5, E17.5 and E18.5 placentaSchmidt et al. (2000), Wang et al. (2011) and Okae et al. (2012)
Imprinted in E12.5 and E18.5 embryo
Mico1M12Not reportedNot reportedNoImprinted in brain, spleen and kidneyLabialle et al. (2008)
Mico1-osM12Not reportedNot reportedNoImprinted in brain, spleen and kidneyLabialle et al. (2008)
Meg3/Gtl2M12YesImprintedYesImprinted in E13.5 and E17.5 placentaMiyoshi et al. (1998) and Wang et al. (2011)
Imprinted in E8.5 and E12.5 embryos and adult brain
Rtl1as microRNAsM12YesImprintedNoImprinted in E13.5 placentaOkae et al. (2012)
Rtl1/Peg11P12YesImprintedYesImprinted in placenta and embryonic brainSeitz et al. (2003), Sekita et al. (2008) and Wang et al. (2011)
RianM12YesImprintedNoImprinted in E13.5 and E17.5 placentaHatada et al. (2001), Wang et al. (2011) and Okae et al. (2012)
miR127M12YesImprintedNoImprinted in embryoSeitz et al. (2003)
miR136M12Not reportedNot reportedNoImprinted in embryoSeitz et al. (2003)
MirgM12YesImprintedNoImprinted in E13.5 and E17.5 placentaSeitz et al. (2003), Wang et al. (2011) and Okae et al. (2012)
AK050713M12YesImprintedNoImprinted in E13.5 placenta and parthenogenetic mouse embryonic fibroblastsHagan et al. (2009) and Okae et al. (2012)
AK053394M12Not reportedNot reportedNoImprinted in parthenogenetic mouse embryonic fibroblastsHagan et al. (2009)
Dio3P12YesConflicting dataNoImprinted in placenta and embryoHernandez et al. (2002), Tsai et al. (2002), Yevtodiyenko et al. (2002) and Okae et al. (2012)
Biallelic in E13.5 placenta
CmahM13E13.5: noUnconfirmedNoImprinted in E17.5 placentaBrideau et al. (2010a) and Okae et al. (2012)
E17.5: yes?Biallelic in E17.5 brain
Not expressed in E13.5 placenta
Drd1aM13E13.5: noUnconfirmedNoImprinted in E17.5 placentaBrideau et al. (2010a) and Okae et al. (2012)
E17.5: yes?Biallelic in E17.5 brain
Not expressed in E13.5 placenta
Pde4dP13Not reportedNot reportedNoAllelic bias in E9.5 embryoBabak et al. (2008)
Htr2aM14Not reportedNot reportedNoImprinted in brain, ovary and embryonic eyeKato et al. (1998)
Kcnk9M15Not reportedNot reportedNoImprinted in embryo and adult brainRuf et al. (2007)
Peg13P15Yes (low)Not reportedNoImprinted in brainSmith et al. (2003) and Davies et al. (2004)
Trappc9M15Not reportedNot reportedNoImprinted in neonatal brainWang et al. (2008)
Slc38a4P15YesImprintedNoImprinted in E13.5, E15.5 and E17.5 placentaMizuno et al. (2002), Smith et al. (2003), Wang et al. (2011) and Okae et al. (2012)
Imprinted in embryo and adult (except liver)
Fbx040M16E13.5: noUnconfirmedNoImprinted in E17.5 placentaBrideau et al. (2010a) and Okae et al. (2012)
E17.5: yes?Biallelic in E17.5 brain
Not expressed in E13.5 placenta
Pde10aM17YesImprintedNoImprinted in E17.5 placentaWang et al. (2011)
Slc22a3M17YesImprintedYesImprinted in E11.5, E13.5 and E15.5 placentaZwart et al. (2001a) and Okae et al. (2012)
Slc22a2M17NoNoPreviously reported placental imprinting at E11.5, but biallelic at E15.5Verhaagh et al. (1999), Zwart et al. (2001a), Hudson et al. (2011), Wang et al. (2011) and Okae et al. (2012)
Subsequently expression shown to be restricted to visceral yolk sac
AirnP17YesImprintedYesImprinted in E13.5 and E17.5 placentaWutz et al. (1997), Lyle et al. (2000), Wang et al. (2011) and Okae et al. (2012)
Igf2rM17YesImprintedYesImprinted in E13.5 and E17.5 placenta, and E15 embryosBarlow et al. (1991), Lerchner & Barlow (1997) and Wang et al. (2011)
QpctM17Yes (decidua)Conflicting dataNoPreviously reported placental imprinting probably due to contamination with decidual cellsBrideau et al. (2010a) and Okae et al. (2012)
Biallelic in E9.0 placenta
ImpactP18YesImprintedNoImprinted in E17.5 placentaOakey et al. (1995), Hagiwara et al. (1997) and Wang et al. (2011)
Imprinted in brain
Tbc1d12P19Not reportedNot reportedNoAllelic bias in E9.5 embryoBabak et al. (2008)
Ins1P19Conflicting dataConflicting dataNoImprinted in yolk sacGiddings et al. (1994) and Deltour et al. (2004)

While imprinted genes have traditionally been described as genes that exhibit monoallelic expression in a parent-of-origin-dependent manner (Mochizuki et al. 1996, Pfeifer 2000, Ferguson-Smith & Surani 2001, Reik & Walter 2001), such a definition belies the complex expression patterns exhibited by imprinted genes, with many displaying preferential, rather than strict monoallelic, expression of parental alleles (Khatib 2007). Some genes are imprinted in all cell types, while others are imprinted in only a subset (Deltour et al. 1995, Hu et al. 1998, Yu et al. 1998, Charalambous et al. 2003, Dockery et al. 2009). In particular, a number of genes imprinted in the placenta are not imprinted in the embryo (Hudson et al. 2010, Okae et al. 2012). Thus, genomic imprinting more accurately describes the complete or partial parental-allele-biased expression of a gene in one or more cell types.

Development and structure of the mouse placenta

The development of the mouse placenta and the characteristics and functions of the trophoblast cell types have been extensively reviewed (Rossant & Cross 2001, Watson & Cross 2005). Here, we briefly describe key features of placental development in the mouse relevant to this review.

The trophoblast is the first discernable lineage to arise during embryogenesis, which by E3 of development forms a monolayer of trophectoderm encasing the inner cell mass (ICM; Fig. 1A). Following implantation at E4.5, the trophoblast cells overlying the ICM proliferate inwards to form the extraembryonic ectoderm and outwards to form the ectoplacental cone (Fig. 1B). Expansion and differentiation of the ectoplacental cone gives rise to the junctional zone, with cells at the maternal edge undergoing endoreduplication and forming a monolayer of parietal trophoblast giant cells (P-TGCs), although only half of this population of TGCs is derived from ectoplacental cone precursors (Simmons et al. 2007). Proliferation of the extraembryonic ectoderm generates the chorionic epithelium that initially forms a flat ‘chorionic plate’ at the base of the placenta and eventually gives rise to the labyrinth layer (Fig. 1C).

Figure 1
Figure 1

Major stages of placental development in the mouse. (A) Before implantation, the blastocyst comprises a monolayer of trophectoderm encasing the inner cell mass (ICM). (B) Proliferation of the trophoblast overlying the ICM forms the extraembryonic ectoderm and ectoplacental cone. (C) By mid gestation, expansion and differentiation of the ectoplacental cone forms the junctional zone with proliferation of the extraembryonic ectoderm generating the chorionic epithelium and eventually the labyrinth layer. The mature mouse placenta comprises at least eight trophoblast-derived cell types contributing to the fetal-derived labyrinth layers and junctional zone. Dec, maternal decidua; Jz, junctional zone; Lab, labyrinth; SpT, spongiotrophoblast; SpA-TGC, spiral artery-associated trophoblast giant cell; P-TGC, parietal trophoblast giant cell; C-TGC, canal trophoblast giant cell; S-TGC, trophoblast giant cell; SynT-I and SynT-II, syncytiotrophoblast layers I and II.

Citation: REPRODUCTION 145, 5; 10.1530/REP-12-0511

By midgestation (∼E12.5), the mouse placenta comprises the labyrinth and junctional zones that together form the fetal–placenta, with proliferation and remodelling of the endometrial lining of the uterine wall at the implantation site forming the maternal decidua. At least eight trophoblast-derived cell types contribute to the fetal–placenta (John & Hemberger 2012), including four TGC subtypes with characteristic gene expression profiles and spatial localisation (Simmons et al. 2007). A monolayer of P-TGCs lines the implantation site forming a boundary between the fetal junctional zone and maternal decidua. Maternal spiral arteries penetrating the decidua are lined by spiral artery-associated trophoblast giant cells (SpA-TGCs), with canal-associated trophoblast giant cells (C-TGCs) surrounding maternal blood canals traversing the spongiotrophoblast and penetrating the labyrinth layer. A single layer of mononuclear sinusoidal trophoblast giant cells (S-TGCs) replaces the endothelial lining of maternal blood sinuses in the labyrinth through which maternal blood is drained from the placenta (Simmons & Cross 2005, Simmons et al. 2007).

In the labyrinth, a bilayer of multinucleated syncytiotrophoblast cells formed by cell fusion completes the characteristic trilaminar cellular structure along with the S-TGCs (Rossant & Cross 2001, Simmons & Cross 2005, Watson & Cross 2005, Simmons et al. 2008a). The junctional zone comprised spongiotrophoblast and glycogen cells, both of which express trophoblast-specific protein alpha (Tpbpa), which can be consequently used to identify these cells. Although formation of the junctional zone is essential for completion of embryogenesis (Guillemot et al. 1994), the precise functions of the two junctional zone cell types remain to be confirmed experimentally. Expression of protocadherin 12 (Pcdh12) specifically marks glycogen cells from ∼E7.5 (Bouillot et al. 2005), with stores of glycogen primarily accumulating from E12.5, and migration of glycogen cells into the maternal decidua occurring from ∼E14.5 (Adamson et al. 2002, Coan et al. 2006). These glycogen stores are thought to provide a source of energy for late-gestation embryonic growth and parturition (Coan et al. 2006). In contrast, the spongiotrophoblast cells, which form the bulk of the junctional zone, are thought to perform an endocrine role in synthesising and secreting a range of prolactin-related (Prl) proteins and pregnancy-specific glycoproteins (Psgs) that act to modulate maternal physiology in response to pregnancy (Kromer et al. 1996, Wynne et al. 2006, Simmons et al. 2008b).

UPD and identification of imprinted regions

The purpose of this review is to provide a summary of the current knowledge regarding imprinted gene function in the placenta with respect to the various placental lineages. While the majority of imprinted genes reported are expressed in the placenta (Table 1), the precise spatial and temporal expression patterns have been described for a subset (Table 2).

Table 2

Placental expression patterns of imprinted genes.

GenePlacental expression patternReferences
Zdbf2SpongiotrophoblastHiura et al. (2010)
Sfmbt2Extraembryonic ectoderm (precursor to labyrinth) at E6.5 and E7.5Frankenberg et al. (2007)
Peg10All trophoblast cell typesOno et al. (2006)
Peg1/MestFetal vasculature endotheliumMayer et al. (2000)
Peg3Junctional zone, P-TGCs and a subset of labyrinthine cellsHiby et al. (2001)
H19All trophoblast cell typesSasaki et al. (1995) and Svensson et al. (1998)
Igf2All trophoblast cell types (Labyrinth-specific transcripts from P0 promoter)Redline et al. (1993), Moore et al. (1997) and Constância et al. (2002)
Ascl2Labyrinth and junctional zoneGuillemot et al. (1994, 1995)
Cdkn1cHighly expressed in labyrinth and glycogen cellsTakahashi et al. (2000)
Low expression in spongiotrophoblast cells
Slc22a3Subset of labyrinth cellsVerhaagh et al. (2001) and Zwart et al. (2001a)
Slc22a18LabyrinthTunster et al. (2010)
Phlda2Ectoplacental cone (E5.5), extraembryonic ectoderm and syncytiotrophoblastFrank et al. (1999, 2002)
Plagl1/Zac1LabyrinthArima et al. (2005)
Grb10Fetal endothelium and trilaminar labyrinthCharalambous et al. (2010)
Dlk1Fetal endothelium in labyrinth; some glycogen cellsda Rocha et al. (2007)
Meg3/Gtl2Fetal endothelium and syncytiotrophoblast in labyrinth; P-TGCs and C-TGCsda Rocha et al. (2007)
Rtl1/Peg11Fetal endothelium of labyrinth layerSekita et al. (2008)

The search for imprinted genes with placental functions was initially directed by the observation of placental defects associated with inheritance of monoparental chromosomal regions (Fig. 2A). Such studies suggested the presence of imprinted genes with placental functions residing on proximal chromosomes 2, 7 and 11 and distal chromosome 7 (Cattanach & Kirk 1985, Searle & Beechey 1990, Cattanach et al. 1996, 2004, McLaughlin et al. 1996, 1997). Embryonic growth defects associated with UPD of proximal chromosomes 6 and 18 and distal chromosome 12, in addition to the embryonic lethality associated with UPD of proximal chromosome 17 (Johnson 1974, Winking & Silver 1984, Oakey et al. 1995, Beechey 2000, Georgiades et al. 2000, 2001, Tevendale et al. 2006), may also suggest placental defects.

Figure 2
Figure 2

Chromosomal locations of genes expressed and imprinted in the mouse placenta. (A) Genes with confirmed imprinted expression in the mouse placenta that map to chromosomal regions associated with embryonic and/or placental phenotypes after monoparental chromosomal inheritance. (B) Genes with confirmed expression in the mouse placenta that map outside chromosomal regions associated with placental and/or embryonic phenotypes. P, placental phenotype; E, embryonic phenotype; L, embryonic lethality; PN, post-natal phenotype. Adapted from www.mousebook.org/catalog.php?catalog=imprinting.

Citation: REPRODUCTION 145, 5; 10.1530/REP-12-0511

Distal chromosome 7

The most extensively characterised of all imprinted regions in the mouse is distal chromosome 7. Maternal UPD of this region results in impaired fetal and placental growth, with death by E17.5. Paternal UPD of the same region results in a loss of the placental junctional zone and embryonic developmental delay and lethality by E10.5 (Searle & Beechey 1990, McLaughlin et al. 1996, 1997). Two mechanistically distinct imprinted domains, IC1 and IC2, are located on distal chromosome 7, with imprinting of each domain regulated through independent mechanisms.

The IC1 domain comprises the paternally expressed Igf2, Igf2as and Ins2 genes and the maternally expressed non-coding H19 RNA. The function of this domain in placental development has been reviewed recently and extensively (Lefebvre 2012, Sandovici et al. 2012); therefore, we will give a brief review here. Igf2 is widely expressed in the placenta, with transcription of murine Igf2 initiated from four promoters; P1, P2 and P3 driving expression in fetal endothelium, TGCs, spongiotrophoblast and, most highly, in glycogen cells, with a P0 transcript driving additional expression specifically in labyrinthine cell layers. Studies have been undertaken for both complete loss of function of Igf2 and isolated loss of the P0 transcript. Loss of all paternal Igf2 transcripts results in reduced placental weight, attributed to a disproportionate loss of the labyrinth layer and an 80% loss of the glycogen cell lineage, with reduced staining for placental glycogen. Loss of only the P0 transcript results in a proportionate reduction of both labyrinth and junctional zones, despite only 10% of total placental Igf2 transcripts initiating at this promoter. Increased transport efficiency is observed in Igf2P0+/− placentae but not in Igf2+/− placentae, suggesting an adaptive response to the imbalance between demand for nutrients by the growing embryo and supply capacity of the placenta. To some extent, the consequence of elevated Igf2 expression on placental development can be inferred from studies in which the imprinting centre for Igf2 is disrupted. As this entails loss of expression of the mechanistically linked H19 gene, either through direct targeting of H19 or indirectly via loss of the imprint, placental phenotypes may reflect elevated Igf2, loss of H19, loss of the microRNA miR675, contained within H19, or a combination of these changes. Loss of imprinting (LOI) at the H19 domain (H19Δ13) results in fetal overgrowth and placentomegaly with a 2.5-fold expansion of the glycogen cell population. Placental glycogen stores are also significantly increased in mutant placentae at E15.5, but with no significant difference at E18.5, suggesting that these stores are either utilised by the overgrowing embryo or that the mutant placenta is unable to sustain them.

The adjacent IC2 domain contains a number of genes expressed and imprinted in the placenta with LOI of this domain, either through targeted deletion of the imprinting centre or termination of the long non-coding RNA Kcnq1ot1 resulting in placental growth restriction with a compromised junctional zone (Fitzpatrick et al. 2002, Salas et al. 2004, Mancini-Dinardo et al. 2006). Within this domain, the three maternally expressed imprinted genes Ascl2, Cdkn1c and Phlda2 have garnered the most interest with respect to placental development. Ascl2 was the first imprinted gene to be shown to be absolutely required for embryonic viability (Guillemot et al. 1994). Ascl2 switches from biallelic to monoallelic expression in the trophoblast cells at ∼E8.5 (Tanaka et al. 1999). Ascl2 is expressed abundantly in the ectoplacental cone and at lower levels in the chorionic epithelium at E8.5, becoming restricted to a subset of cells at E12.5 with expression undetectable by E18.5 (Rossant et al. 1998). Embryos inheriting a mutant Ascl2 allele from their mother die at midgestation with a complete absence of junctional zone, expanded P-TGC layer and defective labyrinth development (Guillemot et al. 1994, 1995). Ascl2 has since been confirmed to be essential for the differentiation of ectoplacental cone precursors into the established junctional zone cell types but is not essential for differentiation of the labyrinth from chorionic epithelium. The expanded P-TGC layer of Ascl2 mutant placentae suggests a role for Ascl2 in maintaining the junctional zone population by preventing their differentiation into P-TGCs. A reduced labyrinth layer has been proposed to reflect a loss of endocrine signalling emanating from the spongiotrophoblast (Tanaka et al. 1997). Deletion of the region between the IC1 and IC2 domains and encompassing the Th gene (Del7AI) results in a twofold reduction in Ascl2 alongside impaired placental and embryonic growth (Lefebvre et al. 2009, Oh-McGinnis et al. 2011). Mutant placentae are characterised by an expansion of P-TGCs, complete loss of glycogen cells, significant loss of spongiotrophoblast cells and disrupted labyrinth (Oh-McGinnis et al. 2011). This suggests that Ascl2 is required for the development of both the spongiotrophoblast and the glycogen cell lineages, although Phlda2 levels are also twofold elevated in this model and may contribute to the placental phenotype.

Cdkn1c encodes a cyclin-dependent kinase inhibitor that negatively regulates cell proliferation and is highly expressed in P-TGCs, glycogen cells, fetal endothelium, syncytiotrophoblast and some larger S-TGC nuclei dynamically during mid-to-late placental development (Georgiades et al. 2002). Cdkn1c mutant placentae are overgrown on the C57BL/6 strain background with an approximate doubling of spongiotrophoblast and labyrinthine cell number, although TGC and glycogen cell number was found to be unaffected at E17.5 in this early study (Takahashi et al. 2000). We studied Cdkn1c−/+ mutants on a 129S2/SvHsd strain background, and while we also observed profound placental overgrowth, the labyrinth of Cdkn1c mutant placentae was severely disrupted at E18.5 with substantial thrombotic lesions, collagen deposits, impaired vascularisation and a severe S-TGC deficit (Tunster et al. 2011). Similar thrombotic lesions were also reported in late-gestation PatUPD7 placentae rescued from lethality by restoration of Ascl2 gene expression (Rentsendorj et al. 2010). We also observed a reduced junctional zone at E18.5, which we determined reflected a specific loss of the spongiotrophoblast lineage by marker analysis. While we found no alteration in expression of the glycogen cell marker Pcdh12, suggesting that expansion of the glycogen cell population was unaffected by loss of expression of Cdkn1c, expression of Gjb3, a marker of mature glycogen cells, was lower. This finding, coupled with a reduction in placental glycogen stores, might explain why Cdkn1c−/+ mutant embryos have a growth advantage even during late gestation but fail to maintain this increased body weight to term.

The maternally expressed gene pleckstrin homology-like domain family a member 2 (Phlda2) encodes a small cytoplasmic protein (Qian et al. 1997, Frank et al. 2002). Although studies on a closely related gene, Phlda3, suggest a role for these PH domain-only proteins in inhibiting Akt-regulated processes (Kawase et al. 2009), this has not been formally demonstrated for Phlda2. Expression of Phlda2 in the placenta is first detected in the ectoplacental cone following implantation, becoming restricted to the syncytiotrophoblast of the labyrinth layer by E10.5 (Frank et al. 1999). Significant maternal bias of Phlda2 is observed in the placenta and embryonic tissues, with lower level expression and less-stringent imprinting in adult tissues (Qian et al. 1997). Phlda2 null mice exhibit placentomegaly with a disproportionate expansion of the junctional zone and histologically exhibit an abundance of stored glycogen, although no direct quantitation of cell number or glycogen stores was undertaken in this study (Frank et al. 2002). We demonstrated that mice with entopic over-expression of Phlda2 exhibit a disproportionate reduction of the junctional zone with limited glycogen stores and impaired fetal growth during late gestation (Salas et al. 2004, Tunster et al. 2010). Using placental marker analysis, we attributed the reduced size of the junctional zone to a specific loss of spongiotrophoblast cells, with no direct effect on glycogen cell abundance. This suggested the possibility that signals from the spongiotrophoblast modulate glycogen storage (Tunster et al. 2010), although this remains to be shown experimentally. Our unpublished studies on the Phlda2 null placenta also suggest a spongiotrophoblast defect rather than an expansion of the glycogen cell lineage.

Proximal chromosome 6

Two imprinted domains are located in close proximity in the proximal region of chromosome 6. Maternal duplication of the most proximal domain, which contains the paternally expressed Peg10 and Sgce genes, results in embryonic lethality at ∼E11.5. Maternal duplication of the more distal domain, which contains the paternally expressed Mest (Peg1) gene, results in embryonic growth retardation that persists into adulthood (Beechey 2000). Embryonic lethality associated with maternal uniparental inheritance of this region may be attributed to a placental defect as a consequence of loss of the retrotransposon-derived Peg10 (Ono et al. 2006). Peg10 is widely expressed in all trophoblast lineages of the placenta and also in several embryonic tissues including brain and vertebral cartilage. Paternal inheritance of a targeted Peg10 allele results in relatively normal placental development until ∼E8.5. Embryonic death occurs between E9.5 and E10.5 as a consequence of the failure of spongiotrophoblast and labyrinth trophoblast lineages to differentiate from the ectoplacental cone and extraembryonic ectoderm precursors respectively. Formation of P-TGCs is apparently normal. This differs from the Ascl2−/+ phenotype in which this population has expanded. Although glycogen cells were not specifically examined in this study, the complete absence of Tpbpa staining in mutant placenta suggests that these cells also fail to develop. Peg10 thus appears to be required for the differentiation of several trophoblast cell types. Functional analyses in the placenta have not been undertaken for the paternally expressed Sgce and eight maternally expressed genes in the Peg10 domain.

The second imprinted domain on mouse chromosome 6 contains the paternally expressed Mest. Mest is not expressed in trophoblast lineages, with expression restricted to fetal endothelial cells of the labyrinth (Mayer et al. 2000). Loss of function results in a placental weight deficit and late gestation embryonic growth restriction, although placental morphology appears otherwise normal (Lefebvre et al. 1998). Placental functions have not been ascertained for the other genes in this domain.

Distal chromosome 12

Maternal UPD of chromosome 12 results in a placental weight deficit with a proportionate reduction in all three layers, embryonic growth retardation and neonatal lethality. Paternal UPD of chromosome 12 results in placentomegaly affecting all three placental layers from E12.5, with embryos dying during late gestation (Georgiades et al. 2000, 2001). Defective vascularisation of the paternal UPD labyrinth occurs by E15.5, with an increased abundance of glycogen cells at E13.5 that fail to appropriately invade the decidua and do not decline in number towards term as normal (Georgiades et al. 2001). The placental defects can be traced to the most distal region of chromosome 12, with paternal UPD of this region associated with placentomegaly and maternal UPD associated with a placental weight deficit similar to those observed for UPD of the entire chromosome (Tevendale et al. 2006).

The imprinted domain on distal chromosome 12 comprises four paternally expressed protein-coding genes and at least seven maternally expressed non-coding RNAs that give rise to a number of microRNAs (reviewed in Hagan et al. (2009)). Imprinting of the domain is regulated by differential methylation of the intergenic differentially methylated region (IG-DMR), with deletion of this region resulting in biallelic expression of all genes in the domain (Lin et al. 2003).

The paternally expressed Dlk1 marks fetal endothelial cells and a sub-population of glycogen cells (Yevtodiyenko & Schmidt 2006, da Rocha et al. 2007). Dlk1 mutant placentae have a smaller labyrinth area with reduced vascularisation, but no overall effect on placental weight. In the junctional zone, mutant placentae display an increased abundance of pre-glycogen, although no quantitation of glycogen stores was undertaken. A conditional deletion of Dlk1 in labyrinth fetal endothelium does not produce any overt placental phenotype, although placental structure was not analysed in this model (Appelbe et al. 2012).

The paternally expressed Rtl1 is specifically expressed in fetal endothelial cells of the labyrinth. Rtl1 null mice are growth retarded with reduced viability associated with inheritance of the mutation on a pure C57BL/6 background. Rtl1-deficient placentae are characterised by a severely disrupted labyrinth and impaired passive transport capacity (Sekita et al. 2008). Overlapping the paternal expression of Rtl1 is maternal expression of an antisense Rtl1 transcript (Rtl1as) that is processed into multiple microRNAs that target degradation of the paternal Rtl1 transcript (Seitz et al. 2003, Davis et al. 2005). Maternal inheritance of the Rtl1 null allele disrupts expression of Rtl1as from the maternal allele, thus preventing the targeted cleavage of Rtl1 transcripts resulting in over-expression of Rtl1. Elevated Rtl1 expression was associated with placentomegaly characterised by an expanded fetal capillary lumen and defective syncytiotrophoblast, although there was no effect on embryonic weight (Sekita et al. 2008).

Maternal deletion of the Meg3 (Gtl2) promoter and exons 1–5 is associated with LOI of adjacent genes and results in neonatal death but with apparently normal placental development (Zhou et al. 2010). Paternal inheritance of the same Meg3 deletion was associated with impaired fetal and placental growth and downregulation of Dlk1 and Rtl1 in the placenta but not the embryo (Zhou et al. 2010). The paternally expressed Dio3 encodes a type III iodothyronine deiodinase that inactivates thyroid hormones and is expressed on the trophoblast cell types of the labyrinth layer, although imprinted expression is not established until E15.5 (Hernandez et al. 1999, Tsai et al. 2002, Yevtodiyenko et al. 2002, Okae et al. 2012). No phenotypic characterisation has been reported for specifically altered dosage of Dio3, nor the non-coding RNA designated RNA imprinted and accumulated in nucleus (Rian).

Proximal chromosome 11

Maternal UPD of chromosome 11 is associated with embryonic and placental growth retardation with paternal UPD leading to overgrowth of both embryo and placenta (Cattanach & Kirk 1985, Cattanach et al. 1996). Three of the genes located within this domain are expressed biallelically in the placenta (Ddc, Cobl and Commd1). Zrsr1 (U2af1-rs1) resides within intron 1 of Commd1, is paternally expressed in the placenta, and although mice carrying a targeted deletion have been generated, a placental function has not been reported (Hatada et al. 1995, Sunahara et al. 2000).

The most extensively characterised imprinted gene on chromosome 11 is growth factor receptor-bound protein 10 (Grb10). Grb10 expression is restricted to the fetal endothelium, where it is expressed only from the maternal allele, and a subset of trophoblast cells in the labyrinth layer where it is expressed biallelically (Charalambous et al. 2010). Maternal inheritance of a disrupted Grb10 allele results in placental and embryonic overgrowth (Charalambous et al. 2003). The volume occupied by the labyrinth layer was increased by ∼50%, although the potential effect on nutrient transport was not quantified (Charalambous et al. 2010). Paternal transmission of a disrupted Grb10 DMR results in biallelic expression of Grb10 and largely recapitulates the phenotypes associated with maternal UPD of chromosome 11, with placental and embryonic growth retardation that persists into adulthood (Shiura et al. 2009).

Proximal chromosome 17

Maternal inheritance of a deletion of proximal chromosome 17 is associated with embryonic lethality (Johnson 1974, Winking & Silver 1984). This domain contains the maternally expressed IGF2 receptor (Igf2r), a multifunctional receptor that binds a range of ligands (Morgan et al. 1987), and two transporters, Slc22a2 and Slc22a3. Loss of function of Igf2r results in placentomegaly (Wang et al. 1994, Wylie et al. 2003) whereas twofold expression of Igf2r, Slc22a2 and Slc22a3 has no gross effect on placental weights (Wutz et al. 2001). Placental weights were only examined at E17.5 in this study and no histology was reported. It remains possible that there might be an earlier or subtle placental phenotype resulting from elevated Igf2r.

Slc22a3 is expressed exclusively in a subset of cells of the labyrinth layer (Verhaagh et al. 2001, Zwart et al. 2001a), whereas Slc22a2 expression is restricted to the visceral yolk sac (Hudson et al. 2011) and is not expressed in the placenta as previously reported (Zwart et al. 2001a). Slc22a3 null mice are viable and fertile with no overt placental defect (Zwart et al. 2001b, Jonker et al. 2003).

Proximal chromosome 7

Maternal UPD of the proximal domain of chromosome 7 is associated with impaired fetal and placental growth (Searle & Beechey 1990). Functional data exist only for the paternally expressed Peg3 within this domain, which encodes a zinc finger protein and is widely expressed in the junctional zone and P-TGCs, with weaker expression in a subset of labyrinthine cells (Kuroiwa et al. 1996, Relaix et al. 1996, Hiby et al. 2001). A significant placental weight deficit has been reported in response to Peg3 deficiency (Li et al. 1999), but complete characterisation of the placental Peg3 null phenotype has not been reported.

Proximal chromosome 2

Thirteen imprinted genes are located on mouse chromosome 2, although not all are imprinted in the placenta (Table 1). Maternal UPD of an extensive proximal region of chromosome 2 is associated with impaired placental and fetal growth, with paternal UPD of the same region associated with overgrowth of the placenta, but not the embryo (Cattanach et al. 2004). The only imprinted protein-coding gene in this region is the paternally expressed Sfmbt2 (Kuzmin et al. 2008), which suggests that this gene may have a role in promoting placental growth.

Proximal chromosome 18

Maternal and paternal UPD of proximal chromosome 18 is associated with perturbed fetal growth (Oakey et al. 1995), although to date the only imprinted gene reported in this region is the paternally expressed Impact (Hagiwara et al. 1997). No placental characterisation has been reported.

X-linked genes

The paternally inherited X-chromosome is preferentially inactivated in the extraembryonic tissue of mice, and thus, X-linked genes that undergo inactivation can also be considered imprinted in the mouse placenta (Takagi & Sasaki 1975, West et al. 1977). The existence of X-linked, imprinted genes with important placental functions was uncovered by studying mice with an XO karyotype. XO embryos with a paternal X (XpO) display impaired ectoplacental cone expansion during early gestation whereas XO embryos carrying the maternal X (XmO) do not (Ishikawa et al. 2003).

More recent gene targeting studies have identified five X-linked, imprinted genes with placental functions. Esx1 is expressed in cells of the labyrinth layer (Li et al. 1997) with maternal inheritance of a targeted allele resulting in placentomegaly, defective labyrinthine vascularisation and an expansion of the glycogen cell population. The boundary between labyrinth and junctional zones was disrupted, with fluid-filled cysts appearing in the junctional zone in mutant placentae. Consistent with placental insufficiency, Esx1 mutant mice display a late gestation growth restriction alongside post-natal catch-up growth (Li & Behringer 1998).

Cited1 is expressed in all trophoblast cell types of the placenta, with maternal deletion of Cited1 associated with impaired placental growth and a disruption of the border between the junctional zone and labyrinth. The junctional zone of mutant placenta was enlarged with a concomitant decrease in labyrinthine area. Vascularisation of the labyrinth was defective, with increased sinusoidal spaces resulting in a reduced surface area for nutrient transport (Rodriguez et al. 2004). Consistent with placental insufficiency, mutant embryos were asymmetrically growth restricted during late gestation, with the majority of mutants dying in the neonatal period and survivors exhibiting catch-up growth within 8 weeks of birth (Rodriguez et al. 2004, Novitskaya et al. 2011).

The protein-kinase-encoding Nrk is expressed specifically in the junctional zone. Disruption of the maternal copy of Nrk is associated with placentomegaly, with an expansion and disruption of the junctional zone and impaired fetal growth during late gestation. Delivery of litters entirely comprised of mutant conceptuses was significantly delayed, with some pregnant dams dying after failing to deliver by E22, suggesting a role for either the junctional zone or Nrk itself in the induction of labour (Denda et al. 2011).

Deletion of the maternal allele of the ubiquitously expressed Chm impairs placental growth, with reduction of both labyrinthine and junctional zones and an expansion of the P-TGC layer. Vascularisation of mutant placentae was severely disrupted, with thrombotic lesions observed in some mutants and embryonic lethality by E11.5 (Shi et al. 2004).

Plac1 is widely expressed in cells of both labyrinth and junctional zone. Despite escaping complete paternal X inactivation, maternal inheritance of a targeted Plac1 allele results in placentomegaly with an expansion of the junctional zone and disruption of the boundary with the labyrinth layer. Increased TGCs were observed in the labyrinth of mutant placentae, although these cells were not confirmed as S-TGCs (Jackman et al. 2012).

Imprinted genes not associated with UPD placental phenotypes

Uniparental inheritance of some chromosomal regions is not associated with overt placental or embryonic growth defects. Additionally, a small number of imprinted genes have been identified that are not associated with established imprinted domains (Fig. 2B). However, this does not preclude a role for such genes in the formation of a functional placenta and awaits further experimental clarification.

Placental imprinting has been reported only for Zdbf2 on chromosome 1. Zbdf2 is highly expressed in the junctional zone, with conserved imprinting of Zbdf2 in human placentae suggestive of an important function (Hiura et al. 2010). Maternal expression of Magi2 and Htra3 has been recently reported on chromosome 5 (Wang et al. 2011, Barbaux et al. 2012). A placental function for Magi2 has not been investigated, whereas Htra3 is expressed exclusively in decidual cells (Nie et al. 2006). HTRA3 inhibits trophoblast invasion in humans (Singh et al. 2010, 2011), although its function in the murine placenta has not been investigated.

The imprinted domain located within the central region of chromosome 7 is referred to as the Prader–Willi/Angelman syndromes (PWS-AS) cluster in humans due to the involvement of genes in this region in the imprinted PWS/AS. Within this region, Magel2 is expressed in the placenta (Kozlov et al. 2007), with some Magel2 mutants lost relatively early in development, which may suggest a placental defect (Bischof et al. 2007). Paternal expression of Gab1 on chromosome 8 has recently been reported specifically in the placenta (Okae et al. 2012). Gab1 is expressed in cells of both the labyrinth and junctional zone. Homozygous Gab1 deficiency results in a disproportionate loss of labyrinth layer, with embryonic lethality by E18.5, although heterozygous transmission of the deletion has not been examined (Itoh et al. 2000, Sachs et al. 2000, Schaeper et al. 2007). Five imprinted genes have been identified on distal chromosome 9. Rasgrf1 is expressed in the placenta (Dockery et al. 2009), but maternal UPD of the region is associated only with a post-natal growth restriction phenotype (Itier et al. 1998, Clapcott et al. 2003, Cattanach et al. 2004).

Imprinting of three genes on chromosome 10 has been reported, although a placental function has been reported for only the paternally expressed Plagl1 (Zac1) gene, which encodes an anti-proliferative, pro-apoptotic zinc finger protein that interacts with an imprinted gene network including Igf2, H19, Cdkn1c and Dlk1 (Spengler et al. 1997, Piras et al. 2000, Arima et al. 2005, Varrault et al. 2006). Plagl1-deficient placenta is lighter than wild type but otherwise morphologically similar to wild type with normal nutrient transport. Mutant embryos are asymmetrically growth restricted during late gestation, indicative of a placental defect (Varrault et al. 2006).

Imprinting of four distally located genes on chromosome 15 has been reported. Placental functions for three of these genes (Kcnk9, Peg13 and Trappc9) have not been investigated. Slc38a4 encodes a member of the system A amino acid transporters that is paternally expressed specifically in the placenta (Mizuno et al. 2002). Although generation of an Slc38a4 null mouse model has been alluded to in recent publications (Coan et al. 2010, Fowden et al. 2011), a complete characterisation of the phenotype has yet to be published.

Discussion

Our knowledge of the function of imprinted genes in the placenta has advanced considerably since the identification of the first imprinted gene over two decades ago. However, despite the demonstrable importance of imprinted genes in placental development, it is perhaps surprising that placental functions have been characterised in detail for only a minority of these genes (Table 3). Of perhaps greater concern is the assumption that loss-of-function models can be used to formulate hypotheses regarding the function of imprinting in placental development with little acknowledgement that these models fail to address dosage-related function. While loss-of-function models provide invaluable data regarding gene function, they do not address imprint function. ‘LOI’ models have been generated for some imprinted domains but the interpretation of the resulting phenotypes is confounded by the combined effects of both loss of expression and gain-in-expression of multiple imprinted genes. Modelling LOI at the individual gene level is considerably more difficult to achieve, although arguably provides the best evidence to elucidate the advantage of imprinting specific genes while maintaining biallelic expression of others.

Table 3

Phenotypes associated with targeted deletion of imprinted genes.

GeneActive allelePhenotypeReferences
Ascl2MLoss of junctional zone, disrupted labyrinth and embryonic lethalityGuillemot et al. (1994, 1995)
Cdkn1cMPlacentomegalyTakahashi et al. (2000) and Tunster et al. (2011)
Expansion of labyrinth and spongiotrophoblast on C57BL/6 background
Thrombotic lesions, loss of S-TGCs and failure of glycogen cell maturation on 129/Sv background
Dlk1PReduced size and vascularisation of labyrinth; impaired glycogen cell differentiationAppelbe et al. (2012)
Grb10MPlacentomegaly; expansion of labyrinth; embryonic overgrowthCharalambous et al. (2003, 2010)
H19Δ13 (LOI Igf2)MPlacentomegaly and expansion of glycogen cell populationLeighton et al. (1995) and Esquiliano et al. (2009)
H19Δ3MPlacentomegalyKeniry et al. (2012)
Igf2PPlacental weight deficit; disproportionate loss of labyrinth, reduced glycogen storage; intrinsic embryonic growth retardationDeChiara et al. (1990, 1991) and Lopez et al. (1996)
Igf2 P0PPlacental weight deficit; proportionate loss of labyrinth and junctional zone; late gestation embryonic growth restrictionConstância et al. (2002)
Igf2rMPlacentomegaly, fetal overgrowthLau et al. (1994) and Ludwig et al. (1996)
Kcnq1ot1PPlacental and embryonic growth deficitFitzpatrick et al. (2002), Salas et al. (2004) and Mancini-Dinardo et al. (2006)
Decreased junctional zone (due to LOI of IC2 domain genes)
Peg1/MestPPlacental weight deficit, but normal morphologyLefebvre et al. (1998)
Embryonic growth restriction
Peg3PPlacental and embryonic growth deficitLi et al. (1999) and Hiby et al. (2001)
Peg10PFailure of junctional zone and labyrinth layer to formOno et al. (2006)
Embryonic lethal by E10.5
Phlda2MPlacentomegaly and disproportionate expansion of junctional zoneFrank et al. (2002)
Plagl1/Zac1PPlacental weight deficit, but normal morphologyVarrault et al. (2006)
Embryonic growth restriction
Rtl1PDisruption of labyrinth structure, impaired passive transportSekita et al. (2008)

As it stands, loss-of-function studies have identified seven imprinted genes that are required for the proper formation of the labyrinthine tissue and thus likely to be directly important for nutrient transport (Table 3). Imprinted genes also functionally converge on the spongiotrophoblast and giant cell lineages, which perform key endocrine functions in maternal physiology, both locally and systemically. The glycogen cell lineage also appears to be a target for several imprinted genes, most notably Igf2. While loss-of-function models may not provide definitive clues as to the evolution of imprinting, further investigation of these models will provide information on the function of various placental lineages, potentially clarifying the function of these cell types in driving the adaptations in maternal physiology that are required for a successful and healthy pregnancy.

One aspect of placental biology that stands out is the relationship between the spongiotrophoblast and glycogen storage. In several models, glycogen stores in a late-gestation placenta correlate more strongly with the amount of spongiotrophoblast present than with the glycogen cell population. For example, elevated Phlda2 results in a failure of the spongiotrophoblast lineage to expand and a subsequent depletion of glycogen stores, despite no apparent effect on expansion of the glycogen cell population. Similarly, loss of function of Cdkn1c results in a reduction of the spongiotrophoblast lineage alongside a depletion of glycogen stores, but with no overt effect on the glycogen cells. Even with Igf2, where elevated expression is associated with both an increase in glycogen cell number and increased glycogen stores, these stores are not maintained late in gestation, which may reflect the lack of a positive effect of Igf2 on the spongiotrophoblast. We have observed a similar relationship between the spongiotrophoblast lineage and glycogen stores in different strains of inbred mice with C57BL/6 placenta expressing higher levels of spongiotrophoblast-specific markers and carrying considerably higher amounts of glycogen than 129S2/SvHsd placenta (Tunster et al. 2012). Taken together, these data suggest the possibility that signals emanating from the junctional zone promote the uptake and storage of glycogen by the glycogen cell population.

In conclusion, while a great deal of further work is required to assess both the function of imprinted genes in the placenta and the significance of their regulated dosage, current evidence highlights the role of imprinted genes in regulating birth weight both directly and indirectly via placental function. Moreover, the influence of these imprinted genes probably extends beyond early life into adulthood, either as a consequence of the intrinsic activity of the gene or through adaptations that have occurred in the fetus in response to poor in utero growth. Finally, aberrant imprinting in the placenta may have a profound effect on the well-being of the mother during pregnancy. Alterations in the expression of members of this relatively obscure family of genes may therefore have profound and wide reaching consequences for human health.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.

Funding

S J Tunster was supported by the Biotechnology and Biological Sciences Research Council (grant numbers BB/G015465/1 and BB/J015156/1). A B Jensen was supported by a Biotechnology and Biological Sciences Research Council Doctoral Training Grant to Cardiff University.

References

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